Highly Active Antiretroviral Therapy (HAART), where antiretroviral (ARV) drugs are given in combination, has become the standard in treatment of HIV/AIDS. There is growing consensus that combinations of ARV drugs will be essential for an optimally effective non-vaccine biomedical prevention (nBP) product against HIV. The overarching goal of this IPCP-MBP is to develop intravaginal ring (IVR) formulations based on ARV combinations for prevention of sexual HIV transmission, emphasizing the needs of women in the developing world. A number of obstacles have thus far prevented the development of a safe and effective topical combination nBP product, including: lack of an reliable screening process to select an optimal combination; difficulty in formulating combinations for topical delivery; long timelines to advance novel candidates through the clinical trial phase; concern with manufacturability and manufacturing scale-up for complex delivery platforms; and issues with adherence confounding determination of efficacy and safety in clinical trials. This Program, consisting of 5 Projects and 2 Cores, aims to overcome these obstacles by applying an innovative strategy to advance a library of multidrug IVRs through a systematic and rational screening pipeline. An initial lead combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) will undergo a (pre-Phase I) Exploratory Clinical Trial (Project 4) in healthy women to assess pharmacokinetics (Project 1), safety (Project 2), and surrogate efficacy (Project 3). Concurrently, the TDF-FTC lead and 8 alternative ARV IVR formulations will be assessed in a novel screening process using quantitative metrics to select the best-performing candidate, in terms of safety and efficacy, using well-defined, quantitative go/no-go criteria. Methods and capacity to manufacture clinical cGMP lots of the best-performing combination IVR will be developed in the IND-enabling critical path Project (Project 5), allowing rapid advancement of the safest and most efficacious candidate into Phase I clinical trials at the conclusion of the IPCP. The parallel screening and clinical approach accelerates transition of the final lead to post-IPCP Phase I clinical trials: If TDF-FTC is selected, the IND- enabling critical path is completed within the IPCP and Phase I trials can begin; if an alternative combination is selected, the manufacturing and clinical procedures are in place for rapid advancement of the final, safest and most efficacious lead combination IVR into Phase I clinical trials. Successful completion of this work is of exceptional significance because it uses a systematic, scientific pipeline strategy, based on clear, quantitative decision points, for the accelerated, rational development of a lead combination ARV IVR for HIV prevention, and mitigates against learning, years later, that combinations other than TDF-FTC should have been advanced.